Project Summary: Colorectal cancer (CRC) is one of the most common malignancies in the western world. One main problem in the treatment of CRC tumors is the formation of incurable metastases. Mortality is particularly associated with the occurrence of metastases in the liver. There is an urgent need for developing efficacious prevention or treatment approaches for hepatic metastases of CRC. The long-term goal of my laboratory is to understand cellular metabolism under physiological and pathological conditions and to devise creative approaches for the treatment of cancer and metabolic diseases. One fundamental change in cancer is the alteration of glucose metabolism. Cancer cells exhibit high rates of aerobic glycolysis, in which a majority of pyruvate derived from glycolysis is converted to lactate instead of entering mitochondria for oxidative phosphorylation, even in the presence of oxygen. The cellular metabolic mode associated with aerobic glycolysis allows cancer cells to avoid complete oxidation of glucose. As a result, a significant amount of glucose is shunted to metabolic pathways for production of NADPH and metabolic intermediates, which provide the reducing agent and building blocks required for biosynthesis for proliferation. Pyruvate flux into mitochondria can be dramatically enhanced through mitochondrial uncoupling, a process that allows protons to cross the mitochondrial inner membrane without producing ATP. As a result, mitochondrial uncouplers lead to a ?futile? oxidation cycle that promotes complete oxidation of glucose. We hypothesize that safe mitochondrial uncouplers are potent anti-cancer agents. Mitochondrial uncoupling could be induced by uncoupler protein 1 (UCP1), or by chemical uncouplers. Niclosamide is an FDA- approved anthelmintic drug that is a mitochondrial uncoupler. In our published study (Nat. Med. 20: 1263-1269), we demonstrated that niclosamide ethanolamine (NEN), a salt form of niclosamide, is primarily distributed in mouse liver, where it uncouples mitochondria. Oxyclozanide, a veterinary anthelmintic drug, is also a mitochondrial uncoupler with similar pharmacokinetic properties as NEN. The goal of the proposal is to test this novel cancer chemotherapeutic strategy and to find prototype anti- cancer agents for treating hepatic metastasis of colon cancer. Three specific aims are proposed to test our hypothesis using pharmacological (NEN and oxyclozanide) and genetic (ectopic UCP1 expression) approaches in three hepatic metastatic CRC mouse models: (1). an immune competent tumor transplantation model; (2). a patient- derived xenograft (PDX) mouse model; and (3). a genetically modified mouse model (GEMM) model. A positive outcome could have significant impact on cancer chemotherapy in general. The study will also have high translational potential and clinical implication, in particular for treating metastatic colon cancer.